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Natural Product-Based Drug Discovery for COVID-19 Disease

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pharmacology".

Deadline for manuscript submissions: closed (15 January 2023) | Viewed by 22948

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Special Issue Editors

Dr. Priyanka Banerjee

E-Mail Website
Guest Editor

Structural Bioinformatics Group, Charité – Universitätsmedizin Berlin, Berlin, Germany
Interests: Cheminformatics; Insilico toxicity with respects to models alternatives/reduction to animal trials; Computer-aided drug discovery; Drug repositioning; Immunoinformatics

Dr. Robert Preissner

E-Mail Website
Guest Editor

Institute of Physiology, Charité – Universitätsmedizin Berlin, Berlin, Germany
Interests: computer-aided drug design;cheminformatics; computational toxicology

Special Issue Information

Dear Colleagues,

Natural products (NPs) from botanicals are single chemical compounds, substances or mixtures produced by a living organism found in nature that usually exhibit has a pharmacological activity that can be useful in pharmaceutical drug discovery and design. Natural products have played a key role in drug discovery for infectious diseases. Natural products have been a valuable source of drug regimens that form the cornerstone of modern pharmaceutical care. It has been estimated that approximately over half of the pharmaceuticals in clinical use today are derived from natural products. The novel coronavirus disease 2019 (COVID-19) pandemic which started in December 2019 represents an unprecedented threat to public health worldwide. Several clinical cases and in vitro and in vivo results suggest that some anti-inflammation and antivirus drugs have the potential to be prophylactic candidates.

In this issue, we aim to provide a platform for sharing findings and having a discussion around the application of natural products, natural product-based drugs, and herbal medicines as potential prophylactics against COVID-19.

Topics include but are not limited to the following:

The role of natural products in the treatment of infectious disease;
The use of natural products as lead compounds in drug discovery for the treatment of COVID-19 disease;
In silico studies investigating natural products in the treatment of COVID-19 disease;
In vitro studies investigating natural products in the treatment of COVID-19 disease;
Clinical or preclinical studies investigating natural products in the treatment of COVID-19 disease;
Real-world evidence (RWE) studies investigating natural products in the treatment of COVID-19 disease;
Research focusing on natural products, SARS-CoV-2, and specific molecular targets and possible mechanisms of action.

Dr. Priyanka Banerjee
Dr. Robert Preissner
Guest Editors

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Keywords

natural products
COVID-19
computational studies
COVID-19 drug discovery

Published Papers (6 papers)

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Research

19 pages, 3015 KiB

Open AccessArticle

Pharmacological Mechanism of NRICM101 for COVID-19 Treatments by Combined Network Pharmacology and Pharmacodynamics

by Sher Singh and Ying-Fei Yang

Int. J. Mol. Sci. 2022, 23(23), 15385; https://doi.org/10.3390/ijms232315385 - 6 Dec 2022

Cited by 3 | Viewed by 3162

Abstract

Symptom treatments for Coronavirus disease 2019 (COVID-19) infection and Long COVID are one of the most critical issues of the pandemic era. In light of the lack of standardized medications for treating COVID-19 symptoms, traditional Chinese medicine (TCM) has emerged as a potentially viable strategy based on numerous studies and clinical manifestations. Taiwan Chingguan Yihau (NRICM101), a TCM designed based on a medicinal formula with a long history of almost 500 years, has demonstrated its antiviral properties through clinical studies, yet the pharmacogenomic knowledge for this formula remains unclear. The molecular mechanism of NRICM101 was systematically analyzed by using exploratory bioinformatics and pharmacodynamics (PD) approaches. Results showed that there were 434 common interactions found between NRICM101 and COVID-19 related genes/proteins. For the network pharmacology of the NRICM101, the 434 common interacting genes/proteins had the highest associations with the interleukin (IL)-17 signaling pathway in the Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses. Moreover, the tumor necrosis factor (TNF) was found to have the highest association with the 30 most frequently curated NRICM101 chemicals. Disease analyses also revealed that the most relevant diseases with COVID-19 infections were pathology, followed by cancer, digestive system disease, and cardiovascular disease. The 30 most frequently curated human genes and 2 microRNAs identified in this study could also be used as molecular biomarkers or therapeutic options for COVID-19 treatments. In addition, dose–response profiles of NRICM101 doses and IL-6 or TNF-α expressions in cell cultures of murine alveolar macrophages were constructed to provide pharmacodynamic (PD) information of NRICM101. The prevalent use of NRICM101 for standardized treatments to attenuate common residual syndromes or chronic sequelae of COVID-19 were also revealed for post-pandemic future. Full article

(This article belongs to the Special Issue Natural Product-Based Drug Discovery for COVID-19 Disease)

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12 pages, 933 KiB

Open AccessArticle

Immune Responses to COVID-19 Vaccines in Patients with Chronic Kidney Disease and Lead Exposure

by Ju-Shao Yen, Yao-Cheng Wu, Ju-Ching Yen, I-Kuan Wang, Jen-Fen Fu, Chao-Min Cheng and Tzung-Hai Yen

Int. J. Mol. Sci. 2022, 23(23), 15003; https://doi.org/10.3390/ijms232315003 - 30 Nov 2022

Viewed by 1440

Abstract

Literature data regarding the response rate to COVID-19 vaccination in chronic kidney disease (CKD) patients remain inconclusive. Furthermore, studies have reported a relationship between lead exposure and susceptibility to viral infections. This study examined immune responses to COVID-19 vaccines in patients with CKD and lead exposure. Between October and December 2021, 50 lead-exposed CKD patients received two doses of vaccination against COVID-19 at Chang Gung Memorial Hospital. Patients were stratified into two groups based on the median blood lead level (BLL): upper (≥1.30 μg/dL, n = 24) and lower (<1.30 μg/dL, n = 26) 50th percentile. The patients were aged 65.9 ± 11.8 years. CKD stages 1, 2, 3, 4 and 5 accounted for 26.0%, 20.0%, 22.0%, 8.0% and 24.0% of the patients, respectively. Patients in the lower 50th percentile of BLL had a lower proportion of CKD stage 5 than patients in the upper 50th percentile BLL group (p = 0.047). The patients in the lower 50th percentile BLL group also received a higher proportion of messenger RNA vaccines and a lower proportion of adenovirus-vectored vaccines than the patients in the upper 50th percentile BLL group (p = 0.031). Notably, the neutralizing antibody titers were higher in the lower 50th percentile than in the upper 50th percentile BLL group. Furthermore, the circulating levels of granulocyte-colony stimulating factor, interleukin-8, monocyte chemoattractant protein-1 and macrophage inflammatory protein-1α were higher in the upper 50th percentile than in the lower 50th percentile BLL group. Therefore, it was concluded that lead-exposed CKD patients are characterized by an impaired immune response to COVID-19 vaccination with diminished neutralizing antibodies and augmented inflammatory reactions. Full article

(This article belongs to the Special Issue Natural Product-Based Drug Discovery for COVID-19 Disease)

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14 pages, 2779 KiB

Open AccessArticle

Mulberry Component Kuwanon C Exerts Potent Therapeutic Efficacy In Vitro against COVID-19 by Blocking the SARS-CoV-2 Spike S1 RBD:ACE2 Receptor Interaction

by Young Soo Kim, Eun-Bin Kwon, Buyun Kim, Hwan-Suck Chung, Garam Choi, Yeoun-Hee Kim and Jang-Gi Choi

Int. J. Mol. Sci. 2022, 23(20), 12516; https://doi.org/10.3390/ijms232012516 - 19 Oct 2022

Cited by 4 | Viewed by 2834

Abstract

There has been an immense effort by global pharmaceutical companies to develop anti-COVID-19 drugs, including small molecule-based RNA replication inhibitors via drug repositioning and antibody-based spike protein blockers related to cell entry by SARS-CoV-2. However, several limitations to their clinical use have emerged in addition to a lack of progress in the development of small molecule-based cell entry inhibitors from natural products. In this study, we tested the effectiveness of kuwanon C (KC), which has mainly been researched using in silico docking simulation and can serve as an effective building block for developing anti-COVID-19 drugs, in blocking the spike S1 RBD:ACE2 receptor interaction. KC is a natural product derived from Morus alba L., commonly known as mulberry, which has known antiviral efficacy. Molecular interaction studies using competitive ELISA and the BLItz system revealed that KC targets both the spike S1 RBD and the ACE2 receptor, successfully disrupting their interaction, as supported by the in silico docking simulation. Furthermore, we established a mechanism of action by observing how KC prevents the infection of SARS-CoV-2 spike pseudotyped virus in ACE2/TPRSS2-overexpressing HEK293T cells. Finally, we demonstrated that KC inhibits clinical isolates of SARS-CoV-2 in Vero cells. Future combinations of small molecule-based cell entry inhibitors, such as KC, with the currently prescribed RNA replication inhibitors are anticipated to significantly enhance the efficacy of COVID-19 therapies. Full article

(This article belongs to the Special Issue Natural Product-Based Drug Discovery for COVID-19 Disease)

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12 pages, 2306 KiB

Open AccessArticle

Effects of Varying Glucose Concentrations on ACE2′s Hypothalamic Expression and Its Potential Relation to COVID-19-Associated Neurological Dysfunction

by Ankita Srivastava and Bashair M. Mussa

Int. J. Mol. Sci. 2022, 23(17), 9645; https://doi.org/10.3390/ijms23179645 - 25 Aug 2022

Cited by 1 | Viewed by 1952

Abstract

The coronavirus disease 2019 (COVID-19) pandemic has negatively impacted millions of lives, despite several vaccine interventions and strict precautionary measures. The main causative organism of this disease is the severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) which infects the host via two key players: the angiotensin-converting enzyme 2 (ACE2) and the transmembrane protease, serine 2 (TMPRSS2). Some reports revealed that patients with glycemic dysregulation could have increased susceptibility to developing COVID-19 and its related neurological complications. However, no previous studies have looked at the involvement of these key molecules within the hypothalamus, which is the central regulator of glucose in the brain. By exposing embryonic mouse hypothalamic neurons to varying glucose concentrations, we aimed to investigate the expression of ACE2 and TMPRSS2 using quantitative real time polymerase chain reaction and western blotting. A significant and time-dependent increase and decrease was observed on the viability of hypothalamic neurons with increasing and decreasing glucose concentrations, respectively (p < 0.01 and p < 0.001, respectively). Under the same increasing and decreasing glucose conditions, the expression of hypothalamic ACE2 also revealed a significant and time-dependent increase (p < 0.01). These findings suggest that SARS-CoV-2 invades the hypothalamic circuitry. In addition, it highlights the importance of strict glycemic control for COVID-19 in diabetic patients. Full article

(This article belongs to the Special Issue Natural Product-Based Drug Discovery for COVID-19 Disease)

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24 pages, 2545 KiB

Open AccessArticle

Molecular Interactions of Tannic Acid with Proteins Associated with SARS-CoV-2 Infectivity

by Mohamed Haddad, Roger Gaudreault, Gabriel Sasseville, Phuong Trang Nguyen, Hannah Wiebe, Theo Van De Ven, Steve Bourgault, Normand Mousseau and Charles Ramassamy

Int. J. Mol. Sci. 2022, 23(5), 2643; https://doi.org/10.3390/ijms23052643 - 27 Feb 2022

Cited by 20 | Viewed by 8244

Abstract

The overall impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on our society is unprecedented. The identification of small natural ligands that could prevent the entry and/or replication of the coronavirus remains a pertinent approach to fight the coronavirus disease (COVID-19) pandemic. Previously, we showed that the phenolic compounds corilagin and 1,3,6-tri-O-galloyl-β-D-glucose (TGG) inhibit the interaction between the SARS-CoV-2 spike protein receptor binding domain (RBD) and angiotensin-converting enzyme 2 (ACE2), the SARS-CoV-2 target receptor on the cell membrane of the host organism. Building on these promising results, we now assess the effects of these phenolic ligands on two other crucial targets involved in SARS-CoV-2 cell entry and replication, respectively: transmembrane protease serine 2 (TMPRSS2) and 3-chymotrypsin like protease (3CLpro) inhibitors. Since corilagin, TGG, and tannic acid (TA) share many physicochemical and structural properties, we investigate the binding of TA to these targets. In this work, a combination of experimental methods (biochemical inhibition assays, surface plasmon resonance, and quartz crystal microbalance with dissipation monitoring) confirms the potential role of TA in the prevention of SARS-CoV-2 infectivity through the inhibition of extracellular RBD/ACE2 interactions and TMPRSS2 and 3CLpro activity. Moreover, molecular docking prediction followed by dynamic simulation and molecular mechanics Poisson–Boltzmann surface area (MMPBSA) free energy calculation also shows that TA binds to RBD, TMPRSS2, and 3CLpro with higher affinities than TGG and corilagin. Overall, these results suggest that naturally occurring TA is a promising candidate to prevent and inhibit the infectivity of SARS-CoV-2. Full article

(This article belongs to the Special Issue Natural Product-Based Drug Discovery for COVID-19 Disease)

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20 pages, 10088 KiB

Open AccessArticle

Molecular Docking and Molecular Dynamics Simulations Discover Curcumin Analogue as a Plausible Dual Inhibitor for SARS-CoV-2

by Shailima Rampogu, Gihwan Lee, Jun Sung Park, Keun Woo Lee and Myeong Ok Kim

Int. J. Mol. Sci. 2022, 23(3), 1771; https://doi.org/10.3390/ijms23031771 - 4 Feb 2022

Cited by 15 | Viewed by 3454

Abstract

Recently, the world has been witnessing a global pandemic with no effective therapeutics yet, while cancer continues to be a major disease claiming many lives. The natural compound curcumin is bestowed with multiple medicinal applications in addition to demonstrating antiviral and anticancer activities. In order to elucidate the impact of curcumin on COVID-19 and cancer, the current investigation has adapted several computational techniques to unfold its possible inhibitory activity. Accordingly, curcumin and similar compounds and analogues were retrieved and assessed for their binding affinities at the binding pocket of SARS-CoV-2 main protease and DDX3. The best binding pose was escalated to molecular dynamics simulation (MDS) studies to assess the time dependent stability. Our findings have rendered one compound that has demonstrated good molecular dock score complemented by key residue interactions and have shown stable MDS results inferred by root mean square deviation (RMSD), radius of gyration (Rg), binding mode, hydrogen bond interactions, and interaction energy. Essential dynamics results have shown that the systemadapts minimum energy conformation to attain a stable state. The discovered compound (curA) could act as plausible inhibitor against SARS-CoV-2 and DDX3. Furthermore, curA could serve as a chemical scaffold for designing and developing new compounds. Full article

(This article belongs to the Special Issue Natural Product-Based Drug Discovery for COVID-19 Disease)

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